Molecular and Transcriptional Basis of CD4+ T Cell Dysfunction during Chronic Infection

Abstract

Summary T cell exhaustion is common during chronic infections. While CD4+ T cells are critical for controlling viral load during chronic viral infections, less is known about their differentiation and transcriptional program. We defined the phenotypic, functional and molecular profiles of exhausted CD4+ T cells. Global transcriptional analysis demonstrated a molecular profile distinct from effector or memory CD4+ T cells and also from exhausted CD8+ T cells, though some common features of CD4+ and CD8+ T cell exhaustion were revealed. We have demonstrated unappreciated roles for transcription factors (TFs) including Helios, type I interferon (IFN-I) signaling and a diverse set of co-inhibitory and costimulatory molecules during CD4+ T cell exhaustion. Moreover, the signature of CD4+ T cell exhaustion was found to be distinct from that of other CD4+ T cell lineage subsets and was associated with TF heterogeneity. This study provides a framework for therapeutic interventions targeting exhausted CD4+ T cells.

Tumor-infiltrating Tim-3+ T cells proliferate avidly except when PD-1 is co-expressed: Evidence for intracellular cross talk

“…This dysfunctional state is also associated with a pattern of transcription factor expression distinct from those of functional effector or memory T cells. 7,8,23,24,34 Functional exhaustion of CD8 C T cells is also observed in cancers and is associated with co-expression of PD-1 and Tim-3 15,16 However, exhaustion of CD4 C effector T cells in cancer is still not well defined. In the cohort of HNSCC patients, we have studied sorted PD-1 hi Tim-3 ¡ and PD-1 C Tim-3 C CD8 C TIL manifested exhausted phenotypes with defective Th1 cytokine production and proliferation (Figs.…”

The Transcription Factor NFAT1 Participates in the Induction of CD4+T Cell Functional Exhaustion during Plasmodium yoelii Infection

“…Infection and Immunity previously published study of gene expression in CD4 ϩ T cells following LCMV infection (17) and found that of genes significantly upregulated in wild-type CD4 ϩ T cells following Plasmodium infection, compared with uninfected controls, there were 13 genes shared by these two data sets, including two well-characterized exhaustionassociated genes, Lag-3 and Maf (Fig. 4C).…”

“…Several recent studies have reported characterization the patterns of gene expression that define exhaustion in CD4 ϩ and CD8 ϩ T cells. These studies have identified genes that comprise a specific gene expression program that shows marked differences from genes activated in other processes of T cell inactivation, such as T cell anergy (17,18). These genes encode inhibitory receptors, such as PD-1, LAG-3, or CTLA-4, and genes involved in the regulation of different aspects of T cell biology, including apoptosis, cell metabolism, control of cytokine expression, and cell-to-cell communication.…”

“…Clonal T cell anergy occurs as a consequence of suboptimal stimulation, and it is characterized by a unique transcriptional program driven, at least in part, by NFAT1 (9,12,16). Exhausted T cells feature a distinct transcriptional program that is not identical to but has some overlap with the T cell anergy program (17,18), suggesting that NFAT1 might also contribute to T cell exhaustion and participate in the induction of the transcriptional program activated following chronic engagement of the T cell receptor.…”

Interfering with Immunity: Detrimental Role of Type I IFNs during Infection

“…Although persistent LCMV infection is known to result from functional T cell exhaustion (reviewed in Ref. 181) associated with elevated PD-1 expression on T cells (182), as well as IL-10 and PD-L1 expression in infected mice (183,184), a role for type I IFNs in this process was poorly understood until recently.…”